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‘Drug binge’ mice reveal why cravings linger

By Peter Aldhous

Drug cravings can persist long after an addict is “clean”, and often cause relapse. Now we are closer to understanding why, with a detailed picture of how the highly addictive drug methamphetamine causes long-lasting changes in key communication pathways between neurons in the brain.

Researchers led by Nigel Bamford of the University of Washington in Seattle, US, gave mice large doses of methamphetamine, equivalent to those taken by addicts during drug binges, to see how this affected communication between cells in the brain’s cortex and those in a region of the brain called the striatum.

Cells in the striatum called spiny neurons receive connections from neurons in the cortex that release the neurotransmitter glutamate. They also receive connections from other neurons in the mid-brain that release dopamine. This second neurotransmitter normally reinforces behaviours that are crucial for survival, such as seeking food.

Long lasting

But the system can be hijacked by addictive drugs, which cause a surge in the release of dopamine.

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When Bamford and his colleagues treated mice with methampethamine on 10 consecutive days, the surge in dopamine caused a reduction in the release of glutamate from the cells in the cortex. This lasted for more than four months of withdrawal from the drug. “That’s years in humans,” says Bamford.

Only when the animals were given another dose of the drug were normal levels of glutamate release restored. This fits with one leading theory of addiction, which suggests that drugs of abuse disrupt the brain’s chemistry so that addicts must keep taking the drugs to try and restore things to normal.

Two of a kind

But why should the surge in dopamine caused by a dose of methamphetamine initially depress the release of glutamate, and later have the opposite effect?

Bamford says the answer lies with another group of cells in the striatum that affect communication between the spiny neurons and the cells in the cortex. These cells, known as interneurons, release the neurotransmitter acetylcholine.

The interneurons have two types of dopamine receptor, called D1 and D2. Initially a drug-induced surge in dopamine stimulates the D2 receptors, which reduces the release of acetylcholine. This in turn inhibits the release of glutamate from the cells projecting from the cortex.

In the addicted brain, however, dopamine begins to stimulate the interneurons’ D1 receptors, which boost the release of acetylcholine.

Switched on

Although other teams have revealed aspects of this puzzle previously, Bamford says this is the first time the pieces have been pulled together into a single study.

“It definitely does tie everything together,” agrees Stephanie Borgland of the University of British Columbia in Vancouver, Canada.

Bamford is now planning further studies of the interneurons. “That’s really where the [addiction] ‘switch’ is,” he suggests.

Trying to block addiction using drugs that target the dopamine receptors would probably cause too many side effects, as dopamine has many functions in the brain. But it may be possible to target other receptors on the interneurons that influence the release of acetylcholine, Bamford says.